US2025122225A1PendingUtilityA1
Masp-2 inhibitors and methods of use
Est. expiryOct 6, 2043(~17.2 yrs left)· nominal 20-yr term from priority
Inventors:Neil S. CutshallMelinda DavisJennifer Lynn GageSara Rebecca GoldsteinDo Yeon KwonRobert Huerta LemusThomas L. LittleMarkus MetzJeremiah H. NguyenPeter Kurt Nollert Von SpechtJennifer TsoungSudheer Babu VaddelaConnor Weidle
C07D 487/04A61K 31/4985C07D 519/00A61P 7/04A61P 37/06A61P 27/00A61P 1/00A61P 9/00A61P 11/00A61P 29/02A61P 13/12A61P 7/02C07D 495/04C07D 471/04
65
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Claims
Abstract
The disclosure provides synthetic compositions useful as inhibitors of mannan-binding lectin-associated serine protease-2 (MASP-2), including inhibitors that selectively inhibit MASP-2 over thrombin, as well as methods for the manufacture and use thereof.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from a substituted or unsubstituted C 6 -C 10 aryl and a substituted or unsubstituted 5-10-membered heteroaryl consisting of a 5-10-membered monocyclic or bicyclic ring system comprising at least one aromatic ring and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or
R 1 and R 6 , together with the carbon to which they are attached, form a C 3 -C 6 cycloalkyl fused to a 5-10-membered heteroaryl or C 6 -C 10 aryl, wherein the 5-10-membered heteroaryl or C 6 -C 10 aryl, of the C 3 -C 6 cycloalkyl fused to the 5-10-membered heteroaryl or C 6 -C 10 aryl, is substituted or unsubstituted, and wherein the C 3 -C 6 cycloalkyl, of the C 3 -C 6 cycloalkyl fused to a 5-10-membered heteroaryl or C 6 -C 10 aryl, is substituted or unsubstituted;
R 2 is hydrogen or C 1 -C 3 alkyl, or R 2 and L, together with the nitrogen to which they are attached, form a substituted or unsubstituted 3-6-membered heterocyclyl;
L is —(CR 8a R 8b ) n —, wherein each —(CR 8a R 8b )— is the same or is different;
R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 5-6-membered saturated or unsaturated heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl, halogen, and cyano;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, and substituted or unsubstituted benzyl, or R 4 and R 5 , together with the carbon to which they are attached, form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 5-6-membered cycloalkenyl;
R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 3 -cycloalkyl, and cyano;
R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 5-6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl fused with aryl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted C 6 -C 10 aryl fused with C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-9-membered heteroaryl, substituted or unsubstituted 5-9-membered heteroaryl fused with C 5 -C 6 cycloalkyl, alkoxy, and halogen, and when R 7 is hydrogen, n is 0;
R 8a and R 8b are each independently selected from the group consisting of hydrogen, C 1 -C 4 linear alkyl, C 3 -C 4 branched alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, hydroxyalkyl, and alkoxy; or R 8a and R 8b together, with the carbon to which they are attached, form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 3-6-membered heterocyclyl; or
n is 3, one of R 8a or R 8b from a first carbon is a bridging —CH 2 — to a third carbon, and one of R 8a or R 8b from the third carbon is absent, to form a 1,3-cyclobutylene; and
n is 0, 1, 2, 3, or 4, and
wherein when one or more chiral center is present, each chiral center has (R) stereochemistry, (S) stereochemistry, or is a mixture thereof.
2 . The compound of claim 1 , wherein at least one of R 3 , R 4 , and R 5 is not hydrogen, and R 3 is not Cl when R 1 is
3 . The compound of claim 1 , wherein the compound is selected from Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), or a combination thereof, wherein:
4 . (canceled)
5 . (canceled)
6 . The compound of claim 1 , wherein R 6 is methyl or hydrogen.
7 . (canceled)
8 . (canceled)
9 . The compound of claim 1 , wherein R 6 and R 1 , together with the carbon to which they are attached, form a C 3 -C 6 cycloalkyl fused to a substituted or unsubstituted 5-10-membered heteroaryl, or a C 3 -C 6 cycloalkyl fused to a substituted or unsubstituted C 6 -C 10 aryl,
wherein the C 3 -C 6 cycloalkyl is unsubstituted, or is substituted with C 1 -C 3 alkyl, alkoxy, or halogen, and wherein the compound has Formula (I-B):
wherein m is 1 or 2.
10 .- 12 . (canceled)
13 . The compound of claim 1 , wherein R 1 is unsubstituted or substituted C 6 -C 10 aryl, wherein the substituted C 6 -C 10 aryl is substituted with one or more of R 1A , R 1B , R 1C , R 1D , and R 1E , wherein R 1A , R 1B , R 1C , R 1D , and R 1E are each independently selected from the group consisting of hydrogen, C(═NH)NH 2 , C(═NH)NHC(═O)OR 8 , C(═NOC(═O)R 8 )NH 2 , C(═NOC(═O)OR 8 )NH 2 , C(═NOH)NH 2 , C(═NH)NHC(═O)NHC(═O)N(CH 3 )R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , SR 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 , OC(O)R 9 , OC(O)OR 9 , OC(O)NR 9 R 10 , NR 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(═NR 9 )NR 10 R 11 , C(═NOR 9 )NR 10 R 11 , C(═NOC(O)R 9 )NR 10 R 11 , C(═NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(═NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 6-10 arylalkyl, substituted or unsubstituted C 6-10 aryloxy, substituted or unsubstituted C 6-10 arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted 4-10-membered heterocyclyl,
wherein R 8 , R 9 , R 10 , R 11 , and R 12 , are, at each occurrence, independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, C 1 -C 6 alkoxy, aryl, arylalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 10 cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl,
wherein R 13 is a C 6 -C 10 aryl or 5-10-membered heteroaryl, unsubstituted or substituted with CH 2 OC(═O)CH 3 ,
wherein when any one of R 1A , R 1B , R 1C , R 1D , and R 1E is a substituted C 6-10 aryl, a substituted C 6-10 arylalkyl, a substituted C 6-10 aryloxy, a substituted C 6-10 arylalkoxy, a substituted 5-10 membered heteroaryl, a substituted C 3 -C 10 cycloalkyl, or a substituted 4-10 membered heterocyclyl, the R 1A , R 1B , R 1C , R 1D , or R 1E is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(═NR e )NR f R g , NR e C(═NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 R f , S(O) 2 NR e R f and oxo, wherein R e , R f , R g , and R h are, at each occurrence, independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, C 1 -C 6 alkoxy, aryl, arylalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 10 cycloalkyl, heterocyclyl, and heteroaryl.
14 .- 18 . (canceled)
19 . The compound of claim 1 , wherein R 1 is an unsubstituted or substituted 5-10-membered heteroaryl, wherein the substituted 5-10-membered heteroaryl is substituted with one or more of R 1A , R 1B , R 1C , R 1D , and R 1E , and wherein the R 1A , R 1B , R 1C , R 1D , and R 1E are each independently selected from the group consisting of hydrogen, C(NH)NH 2 , C(═NH)NHC(═O)OR 8 , C(═NOC(═O)R 8 )NH 2 , C(═NOC(═O)OR 8 )NH 2 , C(═NOH)NH 2 , C(═NH)NHC(═O)NHC(═O)N(CH 3 )R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , SR 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 , OC(O)R 9 , OC(O)OR 9 , OC(O)NR 9 R 10 , NR 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(═NR 9 )NR 10 R 11 , C(═NOR 9 )NR 10 R 11 , C(═NOC(O)R 9 )NR 10 R 11 , C(═NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(═NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 6-10 arylalkyl, substituted or unsubstituted C 6-10 aryloxy, substituted or unsubstituted C 6-10 arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted 4-10 membered heterocyclyl, wherein the C 3 -C 10 cycloalkyl and 4-10 membered heterocyclyl can be a fused, bridge, or spiro ring system,
wherein R 8 , R 9 , R 10 , R 11 , and R 12 , are, at each occurrence, independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, C 1 -C 6 alkoxy, aryl, arylalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 10 cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl,
wherein R 13 is a C 6 -C 10 aryl or 5-10-membered heteroaryl, unsubstituted or substituted with CH 2 OC(═O)CH 3 ,
wherein when any one of R 1A , R 1B , R 1C , R 1D , and R 1E is a substituted C 6-10 aryl, a substituted C 6-10 arylalkyl, a substituted C 6-10 aryloxy, a substituted C 6-10 arylalkoxy, a substituted 5-10 membered heteroaryl, a substituted C 3 -C 10 cycloalkyl, or a substituted 4-10 membered heterocyclyl, the R 1A , R 1B , R 1C , R 1D , or R 1E is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(═NR e )NR f R g , NR e C(═NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 R f , S(O) 2 NR e R f and oxo, wherein R e , R f , R g , and R h are, at each occurrence, independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, C 1 -C 6 alkoxy, aryl, arylalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 10 cycloalkyl, heterocyclyl, and heteroaryl.
20 .- 24 . (canceled)
25 . The compound of claim 1 , wherein R 1 is selected from the group consisting of:
26 . (canceled)
27 . The compound of claim 9 , wherein R 1 has one of the structures:
and
wherein R 1a , R 1b , and R 1c are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, amino, aminylalkyl, alkoxy, and halogen, and wherein R 1d is selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
28 .- 37 . (canceled)
38 . The compound of claim 1 , wherein R 7 is unsubstituted or substituted C 6 -C 10 aryl, and the substituted C 6 -C 10 aryl is substituted with one or more R 7a , R 7b , R 7c , R 7d , and R 7e , wherein the R 7a , R 7b , R 7c , R 7d , and R 7e are each independently selected from the group consisting of hydrogen, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , SR 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 , OC(O)R 9 , OC(O)OR 9 , OC(O)NR 9 R 10 , NR 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(═NR 9 )NR 10 R 11 , C(═NOR 9 )NR 10 R 11 , C(═NOC(O)R 9 )NR 10 R 11 , C(═NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(═NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 6-10 arylalkyl, substituted or unsubstituted C 6-10 aryloxy, substituted or unsubstituted C 6-10 arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted 4-10 membered heterocyclyl, or wherein any two of R 7a , R 7b , R 7c , R 7d , and R 7e are connected to the phenyl at adjacent carbon atoms, and the two R 7a , R 7b , R 7c , R 7d , and R 7e are connected, together with the carbon atoms to which they are attached, to form a substituted or unsubstituted C 3 -C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring comprising 1-4 heteroatoms selected from the group consisting of N, S, and O, fused to the phenyl,
wherein R 9 , R 10 , R 11 , and R 12 , are, at each occurrence, independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy, aryl, arylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3 -C 10 cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl,
wherein R 7a , R 7b , R 7c , R 7d , and R 7e are each substituted with one or more substituents selected from the group consisting of halogen, CN, OR 13 , SR 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , OC(O)R 13 , OC(O)NR 13 R 14 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 C(O)OR 14 , C(═NR 13 )NR 14 R 15 , NR 13 C(═NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , NR 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo when R 7a , R 7b , R 7c , R 7d , or R 7e is a substituted C 1-6 alkyl, substituted C 6-10 aryl, a substituted C 6-10 arylalkyl, a substituted C 6-10 aryloxy, a substituted C 6-10 arylalkoxy, a substituted 5-10 membered heteroaryl, a substituted C 3 -C 10 cycloalkyl, or a substituted 4-10 membered heterocyclyl,
wherein R 13 , R 14 , R 15 , and R 16 are, at each occurrence, independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy, aryl, arylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3 -C 10 cycloalkyl, heterocyclyl, and heteroaryl, and
wherein when one or more chiral center is present, each chiral center has (R) stereochemistry, (S) stereochemistry, or is a mixture thereof.
39 .- 41 . (canceled)
42 . The compound of claim 1 , wherein R 7 is unsubstituted or substituted 5-9-membered heteroaryl, and the substituted 5-9-membered heteroaryl is substituted with one or more of R 7a , R 7b , R 7c , R 7d , and R 7e , wherein the R 7a , R 7b , R 7c , R 7d , and R 7e are each independently selected from the group consisting of hydrogen, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , SR 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 , OC(O)R 9 , OC(O)OR 9 , OC(O)NR 9 R 10 , NR 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(═NR 9 )NR 10 R 11 , C(═NOR 9 )NR 10 R 11 , C(═NOC(O)R 9 )NR 10 R 11 , C(═NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(═NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 6-10 arylalkyl, substituted or unsubstituted C 6-10 aryloxy, substituted or unsubstituted C 6-10 arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted 4-10 membered heterocyclyl, or wherein any two of R 7a , R 7b , R 7c , R 7d , and R 7e are connected to the phenyl at adjacent carbon atoms, and the two R 7a , R 7b , R 7c , R 7d , and R 7e are connected, together with the carbon atoms to which they are attached, to form a substituted or unsubstituted C 3 -C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring comprising 1-4 heteroatoms selected from the group consisting of N, S, and O, fused to the phenyl,
wherein R 9 , R 10 , R 11 , and R 12 , are, at each occurrence, independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy, aryl, arylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3 -C 10 cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl,
wherein R 7a , R 7b , R 7c , R 7d , and R 7e are each substituted with one or more substituents selected from the group consisting of halogen, CN, OR 13 , SR 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , OC(O)R 13 , OC(O)NR 13 R 14 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 C(O)OR 14 , C(═NR 13 )NR 14 R 15 , NR 13 C(═NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , NR 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo when R 7a , R 7b , R 7c , R 7d , or R 7e is a substituted C 1-6 alkyl, substituted C 6-10 aryl, a substituted C 6-10 arylalkyl, a substituted C 6-10 aryloxy, a substituted C 6-10 arylalkoxy, a substituted 5-10 membered heteroaryl, a substituted C 3 -C 10 cycloalkyl, or a substituted 4-10 membered heterocyclyl,
wherein R 13 , R 14 , R 15 , and R 16 are, at each occurrence, independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy, aryl, arylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3 -C 10 cycloalkyl, heterocyclyl, and heteroaryl, and
wherein when one or more chiral center is present, each chiral center has (R) stereochemistry, (S) stereochemistry, or is a mixture thereof.
43 .- 47 . (canceled)
48 . The compound of claim 1 , wherein L is —(CR 8a R 8b ) n —, wherein each —(CR 8a R 8b )— is the same or is different, and wherein n is 1, 2, or 3, or wherein R 2 and L, together with the nitrogen to which they are attached, form a 4-membered heterocyclyl.
49 .- 57 . (canceled)
58 . A compound of Formula (II):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is a substituted or unsubstituted 5-10-membered heteroaryl consisting of a 5-10-membered monocyclic or bicyclic ring system comprising one to eight carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring;
R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl, halogen, cyano, and CD 3 , wherein the substituted C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, and 5-6-membered heteroaryl of R 3 are substituted with methyl, fluoroalkyl, difluoroalkyl, or trifluoroalkyl;
R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and benzyl, and R 5 is hydrogen or methyl; or R 4 and R 5 , together with the carbon to which they are attached, form a substituted or unsubstituted C 3 -C 5 cycloalkyl or a 6-membered cycloalkenyl;
R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl fused with substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl fused with C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-9-membered heteroaryl, substituted or unsubstituted 5-9-membered heteroaryl fused with C 5 -C 6 cycloalkyl, methoxy, and halogen, and when R 7 is hydrogen, n is 0;
L is —(CR 8a R 8b ) n —, wherein each —(CR 8a R 8b )— is the same or is different, wherein R 8a and R 8b are each independently selected from the group consisting of hydrogen, C 1 -C 4 linear or branched alkyl, hydroxyalkyl, and alkoxy, or R 8a and R 8b together with the carbon to which they are attached form a C 3 -C 6 cycloalkyl or a 4-membered heterocyclyl; and
n is 0, 1, 2, 3, or 4, and
wherein when one or more chiral center is present, each chiral center has (R) stereochemistry, (S) stereochemistry, or is a mixture thereof.
59 .- 73 . (canceled)
74 . A compound of Formula (III):
wherein:
R 1A , R 1B , R 1C , R 1D , and R 1E are each independently selected from the group consisting of hydrogen, linear or branched C 1 -C 3 alkyl, linear or branched C 1 -C 3 aminylalkyl, halogen, tetrazolyl, and amidinyl, and wherein at least one of R 1A , R 1B , R 1C , R 1D , and R 1E is not H;
R 3 is hydrogen or halogen;
R 7 is a substituted or unsubstituted C 6 -C 10 aryl, wherein the substituted C 6 -C 10 aryl is substituted with one or more halogen, one or more C 1 -C 3 alkyl, or a combination thereof; and
L is —CH 2 — or —CH 2 CH 2 —, and
wherein when one or more chiral center is present, each chiral center has (R) stereochemistry, (S) stereochemistry, or is a mixture thereof
75 .- 77 . (canceled)
78 . A compound of Formula (IV):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 2 is hydrogen, or R 2 and L, together with the nitrogen to which they are attached, form a substituted or unsubstituted 3-6-membered heterocyclyl;
L is —(CR 8a R 8b ) n —, wherein each —(CR 8a R 8b )— is the same or is different;
R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 5-6-membered saturated or unsaturated heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl, halogen, and cyano;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, and substituted or unsubstituted benzyl, or R 4 and R 5 , together with the carbon to which they are attached, form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 5-6-membered cycloalkenyl;
R 6 is selected from the group consisting of hydrogen and methyl;
R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 5-6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, cycloalkyl fused with substituted or unsubstituted phenyl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted C 6 -C 10 aryl fused with C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-9-membered heteroaryl, substituted or unsubstituted 5-9-membered heteroaryl fused with C 5 -C 6 cycloalkyl, alkoxy, and halogen, wherein when R 7 is hydrogen, n is 0;
R 8a and R 8b are each independently selected from the group consisting of hydrogen, C 1 -C 4 linear alkyl, C 3 -C 4 branched alkyl, C 3 -C 5 cycloalkyl, hydroxyalkyl, and alkoxy, or R 8a and R 8b together, with the carbon to which they are attached, form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 3-6-membered heterocyclyl; and
n is 0, 1, 2, 3, or 4, and
wherein when one or more chiral center is present, each chiral center has (R) stereochemistry, (S) stereochemistry, or is a mixture thereof.
79 .- 92 . (canceled)
93 . A compound of Formula (V):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is a substituted or unsubstituted aryl, or a substituted or unsubstituted 5-10-membered heteroaryl;
R 2 is hydrogen, or R 2 and L, together with the nitrogen to which they are attached, form a substituted or unsubstituted 3-6-membered heterocyclyl;
R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl, halogen, cyano, and CD 3 , wherein the substituted C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, and 5-6-membered heteroaryl of R 3 are substituted with methyl, fluoroalkyl, difluoroalkyl, or trifluoroalkyl;
R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and benzyl, and R 5 is hydrogen or methyl; or R 4 and R 5 , together with the carbon to which they are attached, form a C 3 -C 6 cycloalkyl or a 6-membered cycloalkenyl;
R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl fused with C 6 -C 10 aryl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl fused with C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-9-membered heteroaryl, substituted or unsubstituted 5-9-membered heteroaryl fused with C 5 -C 6 cycloalkyl, methoxy, and halogen, and wherein when R 7 is hydrogen, n is 0;
L is —(CR 8a R 8b ) n —, wherein each —(CR 8a R 8b )— is the same or is different, wherein R 8a and R 8b are each independently selected from the group consisting of hydrogen, C 1 -C 4 linear or branched alkyl, hydroxyalkyl, and alkoxy, or R 8a and R 8b together with the carbon to which they are attached form a C 3 -C 6 cycloalkyl or a 4-membered heterocyclyl; and
n is 0, 1, 2, 3, or 4, and
wherein when one or more chiral center is present, each chiral center has (R) stereochemistry, (S) stereochemistry, or is a mixture thereof.
94 .- 106 . (canceled)
107 . The compound of claim 1 , wherein the salt of the pharmaceutically acceptable salt is selected from the group consisting of trifluoroacetic acid, hydrogen chloride, acetic acid, hydrogen bromide, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, gluconic acid, and a combination thereof.
108 . (canceled)
109 . The compound of claim 1 , having a structure selected from the group consisting of:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
110 . A pharmaceutical composition, comprising a compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
111 . A method for inhibiting MASP-2 in a subject, comprising administering to the subject a compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount effective to inhibit MASP-2.
112 . (canceled)
113 . (canceled)
114 . A method for treating a disease or disorder treatable by inhibiting MASP-2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
115 .- 153 . (canceled)
154 . A method for inhibiting MASP-2 in a subject, comprising administering to the subject a compound of Formula (I):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from a substituted or unsubstituted C 6 -C 10 aryl and a substituted or unsubstituted 5-10-membered heteroaryl consisting of a 5-10-membered monocyclic or bicyclic ring system comprising at least one aromatic ring and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or
R 1 and R 6 , together with the carbon to which they are attached, form a C 3 -C 6 cycloalkyl fused to a 5-10-membered heteroaryl or C 6 -C 10 aryl, wherein the 5-10-membered heteroaryl or C 6 -C 10 aryl, of the C 3 -C 6 cycloalkyl fused to the 5-10-membered heteroaryl or C 6 -C 10 aryl, is substituted or unsubstituted, and wherein the C 3 -C 6 cycloalkyl, of the C 3 -C 6 cycloalkyl fused to a 5-10-membered heteroaryl or C 6 -C 10 aryl, is substituted or unsubstituted;
R 2 is hydrogen, or R 2 and L, together with the nitrogen to which they are attached, form a substituted or unsubstituted 3-6-membered heterocyclyl;
L is —(CR 8a R 8b ) n —, wherein each —(CR 8a R 8b )— is the same or is different;
R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 5-6-membered saturated or unsaturated heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl, halogen, and cyano;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, and substituted or unsubstituted benzyl, or R 4 and R 5 , together with the carbon to which they are attached, form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 5-6-membered cycloalkenyl;
R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 3 -cycloalkyl, and cyano;
R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 5-6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl fused with aryl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted C 6 -C 10 aryl fused with C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-9-membered heteroaryl, substituted or unsubstituted 5-9-membered heteroaryl fused with C 5 -C 6 cycloalkyl, alkoxy, and halogen, and wherein when R 7 is hydrogen, n is 0;
R 8a and R 8b are each independently selected from the group consisting of hydrogen, C 1 -C 4 linear alkyl, C 3 -C 4 branched alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, hydroxyalkyl, and alkoxy; or R 8a and R 8b together, with the carbon to which they are attached, form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 3-6-membered heterocyclyl; or
n is 3, one of R 8a or R 8b from a first carbon is a bridging —CH 2 — to a third carbon, and one of R 8a or R 8b from the third carbon is absent, to form a 1,3-cyclobutylene; and
n is 0, 1, 2, 3, or 4, and
wherein when one or more chiral center is present, each chiral center has (R) stereochemistry, (S) stereochemistry, or is a mixture thereof.
155 . (canceled)Join the waitlist — get patent alerts
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